Phenothiazine compounds



United States Patent PHENOTHIAZINE COR/[POUNDS Wilhelm Alfons Schuler, Bad Hamburg vor der Hohe, Germany, assignor to Chemische Fabrik Promonta, G.m.b.H.

No Drawing. Application February 11, 1957 Serial No. 639,208

6 Claims. (Cl. 260-243) wherein R denotes lower alkyl, R denotes hydrogen, halogen, lower alkyl or lower alkoxy. A denotes methylene or ethylene, B denotes ethylene or propylene, the sum of the number of carbon atoms contained in the radicals A and B being four. Also included in this invention are the nontoxic acid addition salts of the compounds having the above structural formula.

It is an object of this invention to provide compounds which generally depress the vital body functions such as the blood pressure and the pulse and breathing rates. Further, these compounds potentiate the physiological action of narcotics-a property which renders them extremely valuable in surgery.

The compounds of this invention may readily be prepared by reacting a compound having the formula with a compound having the formula A Y-Ofi \N-R1 \B/ III wherein R R A and B are as above defined, and Y is halogen.

The reaction is carried out in the presence of a basic condensing agent such as sodamide, lithium amide, sodium, sodium alcoholate, sodium hydride, and the like, and in the presence of an inert solvent such as benzene, toluene, xylene, cyclohexane, tetralin, decalin, and the like. The free bases obtained by the reaction described above, are converted to nontoxic acid addition salts thereof with inorganic acids or organic acids, in the usual manner.

The following example will serve to illustrate this invention:

EXAMPLE 1 10-(1-ethyl-3-piperidyl) phenothiazine hydrochloride A mixture of 0.25 mole of phenothiazine and 0.31 mole of lithium amide in 250 ml. of tetralin is heated at -175 C. for about two hours, then 0.25 mole of lethyl-3-bromopiperidine in- 150 ml. of tetralin is added over a period of two hours at -175" C. After the addition has been completed, heating is continued at 170-175 C. for three to four hours. After cooling, the product is extracted with aqueous acetic acid and the organic layer is removed. The aqueous layer is made strongly alkaline with sodium hydroxide and the organic base is extracted with ether. The ether is removed, yielding 10-(l-ethyl-3-piperidyl)phenothiazine which distills at 220-225 C./2-3 mm. The hydrochloride is prepared by heating the free base in aqueous hydrochloric acid and allowing the resulting liquid to cool, whereupon the desired substance is obtained, M.P. 230-231 C.

In a corresponding manner, the following compounds were prepared:

10-(1-methyl-4-piperidyl)phenothiazine: Boiling point.

196 C./2-3 mm.; melting point of hydrochloride 244-246 C.

10-( l-methyl-3 -piperidyl) -2-chlorophenothiazine: Boiling point 191/ 0.1 mm.; melting point of hydrochloride 203-206" C.

10( 1-methyl-3 -piperidyl -4-chlorophenothiazine: Boiling point 187-189 C./0.l8 mm.; melting point of picrate 181-183 C. (dec); melting point of hydrochloride 227-230 C. (dec).

10-(1-n-propyl-3-piperidyl)-2-methylphenothiazine: Boiling point -178 C./0.075 mm.; melting point of picrate l69-l71 C.; melting point of oxalate 178- C.

10-( l-n-propyl-3piperidyl) -3-methylphenothiazine: Boiling point 178-179 C./0.10 mm.; melting point of picrate 153-154 C.; melting point of oxalate 164- 166 C.

10( 1-n-propyl-3 -piperidyl) -4-methylphenothiazine: Boiling point 174-175 C./0.l mm.; melting point of picrate 141-143 C. (dec); melting point of oxalate 180-182 C. (dec).

10 (l propyl 3 piperidyl) 2 methoxyphenothiazine: Boiling point 208-210 C./0.4 mm.; melting point of picrate 168-171 C.

10-(l-methyl-3-piperidyl)-3-methoxyphenothiazine: Boiling point -186 C./0.06 mm.; melting point of picrate l94-196 C. (dec).

10-( 1-methyl-4-piperidyl) -2-chlorophenothiazine: Boiling point 198-200 C./2-3 mm.; hydrochloride is bygroscopic, and the melting point thereof could not be determined.

l0( 1-methyl-4-piperidyl) -4-chloropl1enothiazine: Boiling point 194-198 C./ 0.3 mm.; melting point of picrate 180-182" C. (dec); melting point of oxalate 217- 220 C. (dec).

10( 1-methyl-3 -piperidyl phenothiazine:

of hydrochloride 236-238 C.

l0-(l-n-butyl-3-piperidyl)phenothiazine: Boiling point 235-240 C./2-3 mm.; the hydrochloride is hygroscopic, and the melting point thereof cannot be determined.

Melting point Since certain changes may be made in the compounds above described without departing from the scope of this invention, it is intended that all matter contained in the above description shall be interpreted as illustrative, and not in a limiting sense.

I claim:

1. A piperidyl substituted phenothiazine compound selected from the group consisting of compounds of the formula wherein R is lower alkyl and R is selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, and the non-toxic acid addition salts thereof.

References Cited in the file of this patent UNITED STATES PATENTS Robinson et al. Mar. 25, 1952 Schuler Mar. 5, 1957 OTHER REFERENCES Nieschulz et aL: Arzneimittel Forsch, vol. 4, Apr. 1954, pp. 232, 233, 234 and 241.

Viaud: J. Pharm. Pharmacol, vol. 6 (1954), pp. 361 and 364. 

1. A PIPERIDYL SUBSTITUTED A PHENOTHIAZINE COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA 